A Recombinant G Protein Plus Cyclosporine A–Based Respiratory Syncytial Virus Vaccine Elicits Humoral and Regulatory T Cell Responses against Infection without Vaccine-Enhanced Disease

Abstract

Respiratory syncytial virus (RSV) infection can cause severe disease in the lower respiratory tract of infants and older people. Vaccination with a formalin-inactivated RSV vaccine (FI-RSV) and subsequent RSV infection has led to mild to severe pneumonia with two deaths among vaccinees. The vaccine-enhanced disease (VED) was recently demonstrated to be due to an elevated level of Th2 cell responses following loss of regulatory T (Treg) cells from the lungs. To induce high levels of neutralizing Abs and minimize pathogenic T cell responses, we developed a novel strategy of immunizing animals with a recombinant RSV G protein together with cyclosporine A. This novel vaccine induced not only a higher level of neutralizing Abs against RSV infection, but, most importantly, also significantly higher levels of Treg cells that suppressed VED in the lung after RSV infection. The induced responses provided protection against RSV challenge with no sign of pneumonia or bronchitis. Treg cell production of IL-10 was one of the key factors to suppress VED. These finding indicate that G protein plus cyclosporine A could be a promising vaccine against RSV infection in children and older people.

Global epidemiology of non-influenza RNA respiratory viruses: data gaps and a growing need for surveillance

“…Several candidate respiratory syncytial virus and parainfluenza virus vaccines are in various stages of clinical evaluation, [55][56][57][58][59] and assessing the effect of vaccine-induced immune responses in the context of continued viral evolution and the subsequent potential for vaccine escape will be an essential consideration when determining the annual vaccine composition.…”

Neonatal priming and infancy boosting with a novel respiratory syncytial virus vaccine induces protective immune responses without concomitant respiratory disease upon RSV challenge

“…38,39 This is in agreement with our previous finding that CCL17 plays an important role in the migration of G+ CsAinduced iTreg cells into lung tissue in adult mice. 22 Taken together, our findings suggest that G+ CsA immunization in neonatal mice may induce migration of MDSC to the injection site, initially via both IL-6 and CCL17, facilating subsequent iTreg cell induction. [40][41][42] Although we did not find many changes among other cytokines and chemokines, this may be a consequence of examining only one time point.…”

“…The combination of the RSV G protein with CsA (G+ CsA), induced a high level of neutralizing anti-RSV antibodies and induced iTregs in the lung, resulting in a near absence of ERD following the RSV challenge in adult animals. 22 Here, we investigated the safety and efficacy of this novel G + CsA vaccine in young mice with a priming and boosting immunization strategy. As neonates are vulnerable to RSV infection, an earlier RSV vaccination should give greater benefit.…”

“…Importantly it also induced iTreg cells in lungs and a robust response to a subsequent RSV challenge with effective suppression of ERD in an adult murine model. 22 In this study, we tested the G+ CsA vaccine in a strategy of priming neonates and boosting in infancy using a 5-day-oldmouse model. The newborn (5 to 7-days-old) mouse has been demonstrated to correlate best with the stage of immune maturation of human neonates.…”

Immunological Features of Respiratory Syncytial Virus-Caused Pneumonia—Implications for Vaccine Design

“…Moreover, the bacterium-like particle (BLP) technology has also been used to develop a mucosal vaccine by including the F protein as an antigen to protect against hRSV. Such a RSV BLP vaccine reduced virus titers and resulted in higher titers of F-specific IgG in sera from cotton rats and mice challenged with hRSV [116]. Further, a Phase I clinical trial is in progress to assess the safety, reactogenicity and tolerability of two intranasal dose levels of this vaccine [117].…”